This grant proposes the continuation of a series of experiments to investigate the mechanisms of the cerebral damage which occurs as a result of hypothermia, and to explore various approaches toward improving neurological outcome following complex cardiovascular surgery requiring hypothermic circulatory arrest (HCA) or alternative hypothermic strategies. The studies will be carried out in a unique chronic animal model in which cerebral blood flow and vascular resistance, cerebral oxygen and glucose consumption and extraction, epidural temperature, and quantitative EEG can be monitored throughout the acute hypothermic protocol, and for eight hours postoperatively. Behavioral and neurological outcome are assessed daily for one week postoperatively, and awake quantitative EEG recordings obtained postoperatively are compared with preoperative tracings. These outcome measures can then be correlated with intraoperative observations. The first series of experiments with this model showed that low flow cardiopulmonary bypass (LFCPB) results in milder hemodynamic and metabolic perturbations than HCA, and a better neurological outcome. The occurrence of adverse cerebral sequelae correlates inversely with temperature during HCA, and slow recovery of intraoperative QEEG predicts the presence of cerebral damage. Using this model, a prolonged "vulnerable interval" was identified postoperatively, during which cerebral vascular resistance is inappropriately high, and cerebral metabolism is maintained by increased oxygen and glucose extraction. One of the proposed protocols asks whether cerebral injury will occur if oxygen delivery is compromised during this postoperative interval, and whether various cerebral vasodilators can prevent such injury. In experiments with retrograde cerebral perfusion (RCP) in our model, RCP has been shown to result in better outcome than prolonged HCA for 90 minutes at 20C. Further investigation of RCP is proposed: to elucidate its mechanisms of action, optimal temperatures and pressures, and potential benefits in limiting damage from particulate emboli. In addition, this model provides a unique opportunity to evaluate the efficacy of strategies designed to improve cerebral protection: intermittent perfusion, changes in rewarming techniques, and use of pharmacological agents. The assessment of promising strategies may speed clinical implementation of more effective means of preventing cerebral injury as a consequence of surgical correction of complex congenital heart disease in infants, and high-risk thoracic aneurysm surgery in adults.